Diet-induced Metabolic Disease Research Articles

Low-dose Valine Attenuates Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) in Mice by Enhancing Leptin Sensitivity and Modulating the Gut Microbiome

Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD, yet BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. This study investigates the effects of low-dose valine supplementation on MASLD in a high-fat/high-cholesterol diet (HFD) model. Low-dose valine was found to attenuate the progression of MASLD, significantly reducing body weight, liver weight, and eWAT weight, attenuating hyperglycemia and improving serum lipid profiles. It also decreased hyperleptinemia and enhanced hypothalamic leptin sensitivity, leading to reduced food intake. In the eWAT, metabolic flexibility was improved, as indicated by upregulated adipogenesis-related gene expressions and suppressed leptin expression. In the liver, valine improved hepatic leptin sensitivity, alleviated hepatic steatosis, and reduced triglycerides, cholesterol, TNFα, and IL-6 levels. Mechanistically, valine increased hepatic antioxidant capacity and modulated lipid metabolism and antioxidant pathways, downregulating de novo lipogenesis and cholesterol synthesis while increasing fatty acid oxidation, autophagy-related gene expressions. Moreover, hepatic AMPK pathway activity was enhanced, contributing to improved leptin sensitivity and signalling. Additionally, low-dose valine supplementation also modulated the gut microbiome, suggesting a multifaceted approach to managing MASLD.

A weekly 4-methylpyrazole treatment attenuates the development of non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in male mice: Role of JNK.

4-methylpyrazole (4MP, fomepizole) is a competitive inhibitor of alcohol dehydrogenase (ADH) preventing the metabolism of ethylene glycol and methanol, respectively, into their toxic metabolites. 4MP seems also to possess a potential in the treatment of intoxication from other substance, for example, acetaminophen, and to modulate JNK-dependent signalling. Here, we determined if a treatment with 4MP once weekly affects the development of diet-induced non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in C57BL/6 mice. Male C57BL/6 mice (6-8 weeks old, n = 7-8/group) were pair-fed either a liquid control diet (C) or a liquid sucrose-, fat- and cholesterol-rich diet (SFC) for 8 weeks while being concomitantly treated with 4MP (50 mg/kg bw i.p.) or vehicle once a week. Liver damage, inflammatory markers and glucose tolerance were assessed. Moreover, in endotoxin-challenged J774A.1 cells pretreated with 4MP, pro-inflammatory markers were assessed. The concomitant treatment of SFC-fed mice with 4MP attenuated the increase in JNK phosphorylation and pro-inflammatory markers like IFNγ, IL-6 and 3-nitrotyrosine protein adducts in liver tissue found in vehicle-treated SFC-fed mice, while not affecting impairments of glucose tolerance or the increase in portal endotoxin levels. Moreover, a pretreatment of endotoxin-stimulated J774A.1 cells with 4MP significantly attenuated the increases in JNK phosphorylation and pro-inflammatory mediators like IL-6 and Mcp1. Taken together, our results suggest that a treatment with 4MP once weekly attenuates the activation of JNK and dampens the development of non-obese MASLD in mice.

Transcripts with high distal heritability mediate genetic effects on complex metabolic traits.

Although many genes are subject to local regulation, recent evidence suggests that complex distal regulation may be more important in mediating phenotypic variability. To assess the role of distal gene regulation in complex traits, we combined multi-tissue transcriptomes with physiological outcomes to model diet-induced obesity and metabolic disease in a population of Diversity Outbred mice. Using a novel high-dimensional mediation analysis, we identified a composite transcriptome signature that summarized genetic effects on gene expression and explained 30% of the variation across all metabolic traits. The signature was heritable, interpretable in biological terms, and predicted obesity status from gene expression in an independently derived mouse cohort and multiple human studies. Transcripts contributing most strongly to this composite mediator frequently had complex, distal regulation distributed throughout the genome. These results suggest that trait-relevant variation in transcription is largely distally regulated, but is nonetheless identifiable, interpretable, and translatable across species.

Gut Microbiota Dysbiosis, Oxidative Stress, Inflammation, and Epigenetic Alterations in Metabolic Diseases.

Gut dysbiosis, resulting from an imbalance in the gut microbiome, can induce excessive production of reactive oxygen species (ROS), leading to inflammation, DNA damage, activation of the immune system, and epigenetic alterations of critical genes involved in the metabolic pathways. Gut dysbiosis-induced inflammation can also disrupt the gut barrier integrity and increase intestinal permeability, which allows gut-derived toxic products to enter the liver and systemic circulation, further triggering oxidative stress, inflammation, and epigenetic alterations associated with metabolic diseases. However, specific gut-derived metabolites, such as short-chain fatty acids (SCFAs), lactate, and vitamins, can modulate oxidative stress and the immune system through epigenetic mechanisms, thereby improving metabolic function. Gut microbiota and diet-induced metabolic diseases, such as obesity, insulin resistance, dyslipidemia, and hypertension, can transfer to the next generation, involving epigenetic mechanisms. In this review, we will introduce the key epigenetic alterations that, along with gut dysbiosis and ROS, are engaged in developing metabolic diseases. Finally, we will discuss potential therapeutic interventions such as dietary modifications, prebiotics, probiotics, postbiotics, and fecal microbiota transplantation, which may reduce oxidative stress and inflammation associated with metabolic syndrome by altering gut microbiota and epigenetic alterations. In summary, this review highlights the crucial role of gut microbiota dysbiosis, oxidative stress, and inflammation in the pathogenesis of metabolic diseases, with a particular focus on epigenetic alterations (including histone modifications, DNA methylomics, and RNA interference) and potential interventions that may prevent or improve metabolic diseases.

Insufficient FUNDC1-dependent mitophagy due to early environmental cadmium exposure triggers mitochondrial redox imbalance to aggravate diet-induced lipotoxicity

Cadmium (Cd) is a toxic contaminant widely spread in natural and industrial environments. Adolescent exposure to Cd increases risk for obesity-related morbidity in young adults including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite this recognition, the direct impact of adolescent Cd exposure on the progression of MASLD later in life, and the mechanisms underlying these effects, remain unclear. Here, adolescent rats received control diet or diets containing 2 mg Cd2+/kg feed for 4 weeks, and then HFD containing 15% lard or control diet in young adult rats was selected for 6 weeks to clarify this issue. Data firstly showed that HFD-fed rats in young adulthood due to adolescent Cd exposure exhibited more severe MASLD, evidenced by increased liver damage, disordered serum and hepatic lipid levels, and activated NLRP3 inflammasome. Hepatic transcriptome analysis revealed the potential effects of mitochondrial dysfunction in aggravated MASLD due to Cd exposure. Verification data further confirmed that mitochondrial structure and function were targeted and disrupted during this process, shown by broken mitochondrial ridges, decreased mitochondrial membrane potential, imbalanced mitochondrial dynamic, insufficient ATP concentration, and enhanced mitochondrial ROS generation. However, mitophagy is inactively involved in clearance of damaged mitochondria induced by early Cd in HFD condition due to inhibited mitophagy receptor FUNDC1. In contrast, FUNDC1-dependent mitophagy activation prevents lipotoxicity aggravated by early Cd via suppressing mitochondrial ROS generation. Collectively, our data show that insufficient FUNDC1-dependent mitophagy can drive the transition from HFD-induced MASLD to MASH, and accordingly, these findings will provide a better understanding of potential mechanism of diet-induced metabolic diseases in the context of early environmental Cd exposure.

The “crosstalk” between gut microbiota, metabolites and genes in diet-induced hepatic steatosis mice intervened with Cordyceps guangdongensis polysaccharides

Cordyceps guangdongensis, a novel edible mushroom in China, has shown many positive health effects. In this study, we extracted the C. guangdongensis polysaccharides (CGP) from the fruiting bodies, and investigated the mechanism for CGP improved high-fat diet-induced (HFDI) metabolic diseases. We found that CGP notably reduced fat mass, improved blood lipid levels and hepatic damage, and restored the gut microbiota dysbiosis induced by high-fat diet (HFD). Metabolome analyses showed that CGP changed the composition of bile acids, and regulated HFDI metabolic disorder in hepatic tissue. Transcriptome comparison showed that the improvement of hepatic steatosis for CGP was mainly related to lipid and carbohydrate metabolism. Association analysis result revealed that Odoribacter, Bifidobacterium and Bi. pseudolongum were negatively correlated to fat and blood lipid indicators, and were significantly associated with genes and metabolites related to carbohydrate and lipid metabolism. Collectively, these results indicate that CGP may be a promising supplement for the treatment of obesity and related metabolic diseases.

Long Noncoding RNAs in Diet-Induced Metabolic Diseases.

The prevalence of metabolic diseases, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), is steadily increasing. Although many risk factors, such as obesity, insulin resistance, or hyperlipidemia, as well as several metabolic gene programs that contribute to the development of metabolic diseases are known, the underlying molecular mechanisms of these processes are still not fully understood. In recent years, it has become evident that not only protein-coding genes, but also noncoding genes, including a class of noncoding transcripts referred to as long noncoding RNAs (lncRNAs), play key roles in diet-induced metabolic disorders. Here, we provide an overview of selected lncRNA genes whose direct involvement in the development of diet-induced metabolic dysfunctions has been experimentally demonstrated in suitable in vivo mouse models. We further summarize and discuss the associated molecular modes of action for each lncRNA in the respective metabolic disease context. This overview provides examples of lncRNAs with well-established functions in diet-induced metabolic diseases, highlighting the need for appropriate in vivo models and rigorous molecular analyses to assign clear biological functions to lncRNAs.

A novel fatty acid mimetic with pan-PPAR partial agonist activity inhibits diet-induced obesity and metabolic dysfunction-associated steatotic liver disease

ObjectiveThe prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice. MethodsC57Bl/6 mice (6–11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis. ResultsWe found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice. ConclusionsCollectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.

Sex-based differences in short- and longer-term diet-induced metabolic heart disease.

Sex-based differences in the development of obesity-induced cardiometabolic dysfunction are well documented, however, the specific mechanisms are not completely understood. Obesity has been linked to dysregulation of the epitranscriptome, but the role of N6-methyladenosine (m6A) RNA methylation has not been investigated in relation to the sex differences during obesity-induced cardiac dysfunction. In the current study, male and female C57BL/6J mice were subjected to short- and long-term high-fat/high-sucrose (HFHS) diet to induce obesogenic stress. Cardiac echocardiography showed males developed systolic and diastolic dysfunction after 4 mo of diet, but females maintained normal cardiac function despite both sexes being metabolically dysfunctional. Cardiac m6A machinery gene expression was differentially regulated by duration of HFHS diet in male, but not female mice, and left ventricular ejection fraction correlated with RNA machinery gene levels in a sex- and age-dependent manner. RNA-sequencing of cardiac transcriptome revealed that females, but not males may undergo protective cardiac remodeling early in the course of obesogenic stress. Taken together, our study demonstrates for the first time that cardiac RNA methylation machinery genes are regulated early during obesogenic stress in a sex-dependent manner and may play a role in the sex differences observed in cardiometabolic dysfunction.NEW & NOTEWORTHY Sex differences in obesity-associated cardiomyopathy are well documented but incompletely understood. We show for the first time that RNA methylation machinery genes may be regulated in response to obesogenic diet in a sex- and age-dependent manner and levels may correspond to cardiac systolic function. Our cardiac RNA-seq analysis suggests female, but not male mice may be protected from cardiac dysfunction by a protective cardiac remodeling response early during obesogenic stress.

Phocaeicola vulgatus alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA

ABSTRACT Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.

Lusianthridin ameliorates high fat diet-induced metabolic dysfunction-associated fatty liver disease via activation of FXR signaling pathway.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease, but there are few specific medications for it. Lusianthridin, a major phenanthrene component that originates from Dendrobium Sonia, has various in vitro biological functions. In this study, we aimed to evaluate the therapeutic effects of lusianthridin on high-fat diet (HFD)-induced MAFLD as well as to examine the mechanism of its effects. We fed male mice high-fat-diet for 12 weeks to induce MAFLD and then continued to feed them, either with or without lusianthridin, for another six weeks. We found that lusianthridin decreased serum triacylglycerol, hepatic triacylglycerol, and serum low density lipoprotein cholesterol. It also reduced hepatic lipid accumulation based on the results of morphology analysis. Besides, it improved hepatic inflammation as well, including a decrease in serum alanine aminotransferase and a reduction in macrophage and neutrophil infiltration. Mechanistically, surface plasmon resonance, cell thermal shift assay and dual-luciferase report system results suggested that lusianthridin combined with farnesoid X receptor (FXR) ligand binding region and activated its transcriptional activity. Lusianthridin also decreased de no lipogenesis though inhibiting Srebp1c and downstream Scd-1, Lpin1 and Dgat2 expression in a FXR-dependent manner in oleic acid treated L02 cells. Correspondingly, lusianthridin inhibited Srebp1c and downstream lipogenesis in MAFLD liver tissues of mice at both of genetic and protein levels. Finally, the protective effects of lusianthridin on hepatic steaotosis were abolished in Fxr−/− mice. Taken together, our results suggested that lusianthridin attenuated high-fat-diet induced MAFLD via activation the FXR signaling pathway.

Edible Red Seaweed Hypnea asiatica Ameliorates High-Fat Diet-Induced Metabolic Diseases in Mice.

Metabolic diseases, including obesity, diabetes, and fatty liver disease, are dramatically increasing around the world. Seaweed is low in calories and rich in many active ingredients that are necessary for maintaining good health, and is expected to be effective for preventing metabolic diseases. The purpose of this study was to examine the effects of a traditional Japanese edible seaweed Hypnea asiatica (H. asiatica) on obesity, using a mouse model. H. asiatica was dried and powdered, mixed with a high-fat diet, and fed to male C57BL/6J mice for 13 weeks. On the last day of the experiment, blood samples were collected under anesthesia and biochemical parameters such as lipids and adipokines were measured. Liver and adipose tissue were excised, weighed, and oxidant/antioxidant parameters were measured. Some mice were perfused with a fixative solution containing formalin, and tissue specimens were prepared. A glucose tolerance test was used to assess insulin resistance. The inhibition of lipase activity was evaluated in vitro. Thirteen-week supplementation with H. asiatica suppressed body weight gain, body fat accumulation, and blood glucose levels. H. asiatica also improved fatty liver and hypercholesterolemia, and reduced the oxidant and inflammatory parameters of serum and liver. H. asiatica increased fecal triglyceride excretion and polyphenol-rich ethanol extract of H. asiatica inhibited lipase activity in vitro. These results suggest that polysaccharides and polyphenols in H. asiatica may ameliorate obesity and diabetes by inhibiting intestinal fat absorption and reducing oxidative stress and inflammation. H. asiatica may be useful in preventing metabolic diseases such as obesity, diabetes, and fatty liver.

Dietary supplementation with a PPARγ agonist promotes adipocyte hyperplasia and improves high-fat diet tolerance and utilization in grass carp (Ctenopharyngodon idellus)

Due to the wide usage of high-fat diets in aquaculture, improving the ability of fish to utilize high-fat diets is one of the important issues in the field of aquaculture nutrition. Studies in mammals have proven that increasing the number of adipocytes improves high-fat diet-induced metabolic disease, suggesting that promoting adipocyte hyperplasia has potential as a novel nutritional strategy to reverse the negative effects of high-fat diets in farmed fish. To verify this hypothesis, a total of 270 juvenile grass carp (Ctenopharyngodon idellus) (34.57 ± 0.29 g) were randomly divided into 15 net cages, and a PPARγ agonist (rosiglitazone) was added to the high-fat diet to promote PPARγ-mediated adipocyte hyperplasia. The results showed that PPARγ was activated in adipose tissue instead of the liver and muscle, resulting in adipogenesis and healthy adipose tissue remodeling, including an increased ability to store and metabolize fat and decreased lipid accumulation, immune cell penetration and fibrosis, as well as inflammation. In addition, promoting PPARγ-mediated adipocyte hyperplasia significantly reduced the levels of inflammation in serum, liver and muscle (P < 0.05) and significantly reduced the serum contents of total triglycerides, total cholesterol, aspartate aminotransferase and alanine aminotransferase (P < 0.05), indicating that the tolerance of grass carp to high-fat diets was increased. Subsequently, the growth performance and feed efficiency were significantly improved. Meanwhile, hepatic steatosis decreased as a result of reduced lipid absorption and synthesis, and the synthesis of protein in muscle was significantly increased by promoting the ability of muscle to utilize fat. Taken together, activating PPARγ-mediated adipocyte hyperplasia not only increases the tolerance of grass carp to high-fat diets but also promotes the utilization of high-fat diets and increases the protein-sparing effect of fat in grass carp. Our study indicates that targeting PPARγ-mediated adipocyte hyperplasia to change the pattern of adipose tissue expansion is a nutritional strategy to develop feed additives, which are used to reverse the negative effects of high-fat diets and promote the utilization of high-fat diets in farmed fish.

URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease

We recently reported that the selective inhibition of urate transporter-1 (URAT1), which is primarily expressed in the kidneys, ameliorates insulin resistance by attenuating hepatic steatosis and improving brown adipose tissue function in diet-induced obesity. In this study, we evaluated the effects of dotinurad, a URAT1-selective inhibitor, on the hearts of high-fat diet (HFD)-fed obese mice for 16-20weeks and on neonatal rat cardiomyocytes (NRCMs) exposed to palmitic acid. Outside the kidneys, URAT1 was also expressed in cardiomyocytes and indeed worked as a uric acid transporter. Dotinurad substantially attenuated HFD-induced cardiac fibrosis, inflammatory responses, and cardiac dysfunction. Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease.

Dietary ginger polysaccharides (Gps) improve symptoms in hyperlipidemia rats via alterations in gut microbiota

The aim of this research is to investigate lipid-lowering influence of dietary ginger (Zingier officinales Rocs) polysaccharides (GPS) on hyperlipidemia rats. Rat models with hyperlipidemia was established by high-fat food diet (HFD). Comparing to GP-negative model group, GPS attenuated several effects of HFD feeding, including the levels of blood lipid biochemistry, serum inflammatory markers (tumor necrosis factor TNF-a, interleukin IL-6), antioxidant capacity (superoxide dismutase SOD, glutathione peroxidase GSH-Px, total antioxidant capacity T-AOC, propylene dialdehyde MDA), uric acid and immune index. 16 S rDNA gene sequencing of fecal samples showed that GPS increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes; This changes in microbial community structure can help prevent diet-induced metabolic disease. These results suggest that GPs may act on the gut, changing the structure of the gut microbial community, thereby reducing intestinal and systemic inflammation, thus improved metabolic outcomes.

Therapeutic Effect of Prolyl Endopeptidase Inhibitor in High-fat Diet-induced Metabolic Dysfunction-associated Fatty Liver Disease.

Prolyl endopeptidase (PREP) is a serine endopeptidase that participates in many pathological processes including inflammation, oxidative stress, and autophagy. Our previous studies found that PREP knockout exhibited multiple benefits in high-fat diet (HFD) or methionine choline-deficient diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD). However, cumulative studies have suggested that PREP performs complex functions during disease development. Therefore, further understanding the role of PREP in MAFLD development is the foundation of PREP intervention. In this study, an HFD-induced MAFLD model at different time points (4, 8, 12, and 16 weeks) was used to explore dynamic changes in the PREP proline-glycine-proline (PGP)/N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) system. To explore its potential value in MAFLD treatment, saline, or the PREP inhibitor, KYP-2047, was administered to HFD-induced MAFLD mice from the 10th to 16th weeks. PREP activity and expression were increased in HFD-mice compared with control mice from the 12th week onwards, and increased PREP mainly resulted in the activation of the matrix metalloproteinase 8/9 (MMP8/9)-PREP-PGP axis rather than the thymosin β4-meprin α/PREP-AcSDKP axis. In addition, KYP-2047 reduced HFD-induced liver injury and oxidative stress, improved lipid metabolism through the suppression of lipogenic genes and the induction of β-oxidation-related genes, and attenuated hepatic inflammation by decreasing MMP8/9 and PGP. Moreover, KYP2047 restored HFD-induced impaired autophagy and this was verified in HepG2 cells. These findings suggest that increased PREP activity/expression during MAFLD development might be a key factor in the transition from simple steatosis to steatohepatitis, and KYP-2047 might possess therapeutic potential for MAFLD treatment.

Hepatic ELOVL3 is dispensable for lipid metabolism in mice

Very long-chain fatty acid elongase 3 (ELOVL3) catalyzes the synthesis of C20–C24 fatty acids and is highly expressed in the liver and adipose tissues. The deficiency of Elovl3 exhibits an anti-obesity effect in mice, but the specific role of hepatic ELOVL3 in lipid metabolism remains unclear. Here we demonstrate that hepatic Elovl3 is not required for lipid homeostasis or the pathogenesis of diet-induced obesity and hepatic steatosis. We generated Elovl3 liver-specific knockout mice via Cre/LoxP approach, which maintained normal expression of ELOVL1 or ELOVL7 in the liver. Unexpectedly, the mutant mice did not show significant abnormalities in body weight, liver mass and morphology, liver triglyceride content, or glucose tolerance when fed normal chow or even a low-fat diet. Moreover, deletion of hepatic Elovl3 did not significantly affect body weight gain or hepatic steatosis induced by high-fat diet. Lipidomic analysis revealed that the lipid profiles were not significantly altered by the loss of hepatic Elovl3. Unlike its global knockouts, the mice lacking Elovl3 specifically in liver displayed normal expression of genes involved in hepatic de novo lipogenesis, lipid uptake, or beta-oxidation at the mRNA and protein levels. Collectively, our data indicate that hepatic ELOVL3 is dispensable for metabolic homeostasis or diet-induced metabolic disease.

Time-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice

The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD+. Increasing NAD+ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD+ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ treatment for diet-induced metabolic disease in mice. Increasing NAD+ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD+ immediately before the rest phase selectively compromised these responses. Remarkably, timed NAD+ adjusted circadian oscillations of the liver clock until completely inverting its oscillatory phase when increased just before the rest period, resulting in misaligned molecular and behavioral rhythms in male and female mice. Our findings unveil the time-of-day dependence of NAD+-based therapies and support a chronobiology-based approach.

Inulin increases the beneficial effects of rhubarb supplementation on high-fat high-sugar diet-induced metabolic disorders in mice: impact on energy expenditure, brown adipose tissue activity, and microbiota

ABSTRACT Consumption of prebiotics and plant-based compounds have many beneficial health effects through modulation of gut microbiota composition and are considered as promising nutritional strategy for the treatment of metabolic diseases. In the present study, we assessed the separated and combined effects of inulin and rhubarb on diet-induced metabolic disease in mice. We showed that supplementation with both inulin and rhubarb abolished the total body and fat mass gain upon high-fat and high-sucrose diet (HFHS) as well as several obesity-associated metabolic disorders. These effects were associated with increased energy expenditure, lower whitening of the brown adipose tissue, higher mitochondria activity and increased expression of lipolytic markers in white adipose tissue. Despite modifications of intestinal gut microbiota and bile acid compositions by inulin or rhubarb alone, combination of both inulin and rhubarb had minor additional impact on these parameters. However, the combination of inulin and rhubarb increased the expression of several antimicrobial peptides and higher goblet cell numbers, thereby suggesting a reinforcement of the gut barrier. Together, these results suggest that the combination of inulin and rhubarb in mice potentiates beneficial effects of separated rhubarb and inulin on HFHS-related metabolic disease and could be considered as nutritional strategy for the prevention and treatment of obesity and related pathologies.

Tschimganidine reduces lipid accumulation through AMPK activation and alleviates high-fat diet-induced metabolic diseases

Obesity increases the risk of mortality and morbidity because it results in hypertension, heart disease, and type 2 diabetes. Therefore, there is an urgent need for pharmacotherapeutic drugs to treat obesity. We performed a screening assay using natural products with anti-adipogenic properties in 3T3-L1 cells and determined that tschimganidine, a terpenoid from the Umbelliferae family, inhibited adipogenesis. To evaluate the anti-obesity effects of tschimganidine in vivo. Mice were fed either a normal chow diet (NFD) or a high-fat chow diet (HFD) with or without tschimganidine for 12 weeks. Treatment with tschimganidine decreased lipid accumulation and adipogenesis, accompanied by reduced expression of adipogenesis and lipid accumulation-related factors. Tschimganidine significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased that of AKT. Depletion of AMPK relieved the reduction in lipid accumulation resulting from tschimganidine treatment. Moreover, tschimganidine administration drastically reduced the weight and size of both gonadal white adipose tissue (WAT) and blood glucose levels in high-fat diet-induced obese mice. We suggest that tschimganidine is a potent anti-obesity agent, which impedes adipogenesis and improves glucose homeostasis. Tschimganidine can then be evaluated for clinical application as a therapeutic agent.